The goal of this proposal is to characterize a new spontaneous mouse model of motor neuron disease and identify the causative mutation. Motor neuron diseases such as Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophies (SMA) are common in the population and devastating in their severity for the patient. The molecular basis for these diseases is still unclear despite the identification of a handful of genes associated with heritable motor neuron diseases in both animal models and humans. Animal models of these diseases are critical for research on the pathogenic mechanisms to inform the search for therapeutic targets and to provide preclinical models for testing therapies. Many existing animal models of motor neuron diseases are heavily engineered to reproduce the disease phenotype at the expense of accurately reproducing the genetics of the human disease. For example, dominant mutations in SOD1 in humans cause a familial form of ALS, whereas mouse models require overexpression of mutant forms of the human protein to develop a similar phenotype. In contrast, spontaneous mutations in mice identified because of their related phenotypes are not engineered at all and therefore avoid many caveats of transgenic models. For example, spontaneous mouse mutations in Ighmbp2 identified by Dr. Cox, a PI on this proposal, cause a motor neuron disease in mice that directly led to the identification of the genetic basis of Spinal Muscular Atrophy with Respiratory Distress in humans. Recently, we have identified a novel spontaneous recessive mutation in mice that causes a motor neuron disease phenotype. This model displays overt, progressive loss of neuromuscular function, particularly in the hind limbs, with almost complete paralysis by 5-6 months of age. Examination of spinal roots and neuromuscular junctions indicate a motor neuron defect, and examination of motor neuron cell bodies in the spinal cord ventral horn reveals pathology including eosin-rich, ubiquitin-positive inclusions. The pathology and phenotype of this model differ from previously described mouse models, but accurately recapitulates many of the hallmarks of human motor neuron diseases. We therefore propose two aims to study this new model of motor neuron disease. In Aim 1, we will examine the phenotype using an integrated analysis of gross motor performance, electrophysiological characterization, and histology, immunocytochemistry, and electron microscopy to understand the disease progression and pathology in the motor neurons. This information will allow us to accurately correlate the mouse phenotype with related human diseases. In Aim 2, we will use positional cloning techniques to identify the causative mutation. Identifying the underlying genetic defect is critical for understanding the basis of the motor neuron loss. If this mutation is in a known motor neuron disease gene, it is likely to represent a superior animal model of the associated human disease. If the mutation is in a novel gene, it will provide additional mechanistic insights into the molecular pathways that lead to motor neuron disease and also provide a new candidate gene for related human diseases. PUBLIC HEALTH RELEVANCE: Motor neuron diseases such as Amyotrophic Lateral Sclerosis and Spinal Muscular Atrophy are devastating in their severity, but the underlying pathological mechanisms are poorly understood and current therapies are of limited effectiveness. We have identified a new, heritable mouse model of motor neuron disease and propose to clone the gene responsible. This work will add to our understanding of motor neuron diseases, and therefore aid the search for therapeutic targets. In addition, it will either provide a superior animal model for an existing human disease, or more likely, identify a new candidate gene for familial motor neuron diseases in patients.